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Shijiazhuang Sihua Pharmaceutical Group: Relentlessly Pursuing the R&D of “Made-in-China Medicines”

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Media Reports

发布时间：2024-06-07

【概要描述】 “Producing high-quality medicines for the Chinese people has always been the very soul of Shijiazhuang No. 4 Pharmaceutical’s corporate culture, as well as the unwavering commitment of its employees to serving the nation through industry and giving back to society,” said Qu Jiguang, Chairman of the Board of Shijiazhuang No. 4 Pharmaceutical Group. “Science is inherently compassionate. Moving forward, Shijiazhuang No. 4 Pharmaceutical will continue to uphold a people-centered philosophy, relentlessly innovate and develop more accessible, cutting-edge, and targeted ‘Chinese medicines’ that meet clinical needs and safeguard the lives and health of the public.”

Shijiazhuang Sihua Pharmaceutical Group: Relentlessly Pursuing the R&D of “Made-in-China Medicines”

Successfully passed the review!

On May 30, an exciting piece of news spread throughout Shijiazhuang Sihua Pharmaceutical Group (hereinafter referred to as “Shijiazhuang Sihua”): the peritoneal dialysis solution (lactate-based—G4.25%, 2,000 ml) developed by the group has received registration approval from the National Medical Products Administration, signifying that the product’s safety, efficacy, and quality control have been duly reviewed and verified, and it is now authorized for market launch.

Peritoneal dialysis solution can substitute for the kidneys in removing waste products and maintaining electrolyte balance, thereby effectively treating renal failure.

Shijiazhuang Sihua Pharmaceutical R&D Center. File photo.

“This is a new product we have developed based on the unique characteristics of Chinese renal function,” said Dr. Sun Lijie, Executive President of Shijiazhuang Sihua Pharmaceutical and General Manager of its R&D Center. He noted that the differentially expressed genes in human glomeruli between Chinese and Western populations differ substantially, and that the R&D team took these genetic and physiological differences into full consideration throughout the drug’s development process.

Chinese patients have a greater need for “Chinese medicines.” Relevant research indicates that Asian populations differ markedly from non-Asian populations in genetic makeup, physiological and pathological characteristics, lifestyle and dietary habits, and medication adherence. Consequently, directly applying foreign clinical trial data to guide drug use in China lacks a scientific basis and contravenes the principles of safety and efficacy that underpin pharmaceutical evaluation.

Developing and producing more “Chinese medicines” that are tailored to the genetic heritage and physical characteristics of the Chinese population has become the mission that weighs on the hearts of every member of the “Four Medicines” team.

Precision: Screening the most suitable compound from over ten thousand candidates—045

“At the current dosage, no adverse drug reactions have been observed in the study participants, demonstrating a high safety profile!” On the morning of June 3, Dr. Yang Xian, Head of the Innovation Department at Shijiazhuang No. 4 Pharmaceutical R&D Center, said excitedly, holding the clinical data for the new drug SYN-045.

SYN-045 is a first-in-class investigational drug for the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension is a malignant pulmonary vascular disease that can lead to severe complications, including right ventricular failure. Clinical studies have shown that patients who do not receive effective treatment have a one-year survival rate of only 68%, which is why this condition is often referred to as “the cancer of cardiovascular diseases.”

In May 2018, idiopathic pulmonary arterial hypertension, the most typical form of pulmonary arterial hypertension, was included in the “First Batch of Rare Disease Catalogue” jointly formulated by the National Health Commission and four other departments.

According to estimates by the China Charity Federation, there are currently approximately 12 million patients with pulmonary arterial hypertension in China.

The disease burden is severe, yet the pharmacological options and therapeutic modalities available to physicians are limited. Currently, the majority of pulmonary arterial hypertension medications used in China are imported.

Not only are imported drugs expensive, but some patients experience adverse reactions such as nausea, vomiting, dizziness, and peripheral vasodilation after taking them; in severe cases, systemic hypotension may even occur.

In 2017, Shijiazhuang Sihua Pharmaceutical established a new drug development project team for pulmonary arterial hypertension, leveraging the company’s extensive experience in chemical drug R&D with the goal of conquering this “rare disease.”

“The most distinctive feature of a new drug is that it must be better suited to the physical characteristics of Chinese patients; the greatest challenge, however, is ensuring that it causes absolutely no adverse reactions,” Yang Xian explained.

Research personnel, after reviewing the scientific literature, found that genetics is an important factor influencing the onset of pulmonary arterial hypertension; genes such as the bone morphogenetic protein receptor type 2 gene and the prostaglandin synthase gene have been associated with pulmonary arterial hypertension in Chinese individuals.

How can we leverage the genetic characteristics of the Chinese population to precisely identify drug targets?

The project team needs to design entirely new molecular structures, synthesize effective compounds, and then develop these compounds into drugs.

What appears to be a simple process is, in practice, as difficult as scaling the heavens.

The project team must conduct multiple rounds of screening among tens of thousands of compounds to identify more than 100 with strong potential, which will then be subjected to further validation.

Four years later, in 2021, they selected compound No. 45: 045.

Everyone gathered around, excited and gazing at SYN-045 as if it were a newborn baby.

“045” is the identification number for this compound and later became part of the new drug’s name, SYN-045.

A sample of SYN-045 on display at the R&D Center of Shijiazhuang Fourth Pharmaceutical. Photo by Yuan Lipeng, Hebei Economic Daily.

After nearly three years of dedicated effort, SYN-045 has progressed from the laboratory to the production line and entered Phase I clinical trials, bringing it ever closer to patients.

“Recent clinical data submitted in feedback demonstrate that SYN-045 not only lacks the common adverse reactions seen with foreign drugs, but also exhibits superior target specificity and does not cause systemic hypotension, making it truly a superior medication better suited to Chinese patients.” As she spoke these words, Yang Xian’s eyes lit up with enthusiasm, brimming with high expectations for her “baby” project.

Safety: It’s worth investing as much time as necessary.

“How is this batch of data? Has its stability improved?”

On June 3, in the R&D Center laboratory of Shijiazhuang Sihua Pharmaceutical, Zhang Le, head of the Solid Dosage Form Division I, and his colleagues were meticulously comparing data as they worked to optimize the formulation and manufacturing process for a generic cephalosporin dry suspension.

Innovative drugs have become a key focus of biopharmaceutical R&D because they can address the unmet therapeutic needs of major clinical diseases.

In contrast, generic drugs are favored in the pharmaceutical market due to their lower costs and ability to offer patients a wider range of choices.

For this very reason, in recent years the National Health Commission, the Ministry of Industry and Information Technology, the National Intellectual Property Administration, and other relevant departments have successively released three batches of the “Catalogue of Drugs Encouraged for Generic Production.”

Zhang Le and his team have developed a generic dry-mix suspension of cephalosporin, which is an oral, broad-spectrum third-generation cephalosporin primarily used to treat infections caused by various bacteria. Compared with earlier generations of cephalosporin products, it exhibits superior antibacterial efficacy.

Initially, drawing on past experience, R&D progressed rapidly for a time.

However, an unexpected announcement disrupted this trend. On July 14, 2023, the International Agency for Research on Cancer, the World Health Organization, and the Joint FAO/WHO Expert Committee on Food Additives released an assessment report classifying aspartame as a substance that may be carcinogenic to humans.

Aspartame is precisely one of the excipients used in generic drugs to mask the bitter taste of the active ingredient and enhance palatability.

Although experts have also cautioned that the carcinogenicity of aspartame is only “possible” and that daily intake of no more than 40 milligrams per kilogram of body weight remains safe, researchers remain divided over whether to retain or discard it.

The “retention camp” argues that the originator drug contains nine active ingredients; substituting even one of them would necessitate extensive re-evaluation, which is time-consuming, labor-intensive, and likely to delay progress. Moreover, at the time, each dosage unit contained less than 5 milligrams of aspartame—well within the safety threshold—so the originator product continued to be sold normally in overseas markets.

“The Abandonment School” insists that drug development must prioritize safety above all else—no matter how minuscule the risk, it must never be ignored!

The project team discusses the design plan for the new product. Photo by Liu Pengpeng, Hebei Economic Daily.

Differences of opinion are no cause for concern. Zhang Le organized numerous rounds of discussion, during which participants refined their thinking through debate and ultimately reached unanimous agreement to discontinue aspartame and replace it with a new excipient.

This means that a substantial amount of work had to be restarted from the beginning. After conducting nearly one hundred compatibility tests of raw and excipient materials, drug formulation stability tests, and human oral pH tests, the team identified a batch of excipients that are non-toxic, free of adverse side effects, and highly safe.

Following a volunteer-driven taste evaluation, sodium chloride and monosodium glutamate—the primary components of table salt and MSG, respectively—were further selected; their combination effectively masks the pungent odor and bitter taste of the drug.

It is now the 2024 Spring Festival, and R&D has taken six months longer than originally planned.

“For the sake of patient safety, it’s worth investing as much time and resources as necessary!” Zhang Le’s gaze was unwavering behind his glasses.

Innovation: Cloaking Drugs in a Sustained-Release “Magic Coat”

This is a vibrant young team.

At the Shijiazhuang Sihua Pharmaceutical R&D Center, the team leader, Sun Lijie, was born in the 1980s. “Research is about creation—anywhere there’s even the slightest chance, it’s worth a try,” is his favorite saying.

This young leader heads a team of post-80s and post-90s master’s and doctoral graduates—many of them even younger than he is—who have earned the nickname “Magic Squad” for their relentless drive, fearless determination, and repeated breakthroughs in drug discovery and development.

Dressing urapidil sustained-release capsules in a “magic coat” is yet another of their masterpieces.

Urapidil sustained-release capsules are a medication widely used abroad for the treatment of severe hypertension, and Shijiazhuang No. 4 Pharmaceutical has become the first domestic pharmaceutical company to obtain approval for its generic version. Earlier this year, the company’s marketing application for Urapidil sustained-release capsules was accepted by the Center for Drug Evaluation of the National Medical Products Administration.

Hypertension in China has been increasing year by year. According to data from the National Center for Cardiovascular Diseases, approximately 245 million adults in China have hypertension, meaning that about one in every four adults is affected.

To curb the rising prevalence of hypertension, clinicians need more new and effective medications to expand their therapeutic arsenal.

The differences in physical constitution and dietary patterns between Chinese individuals and those from Western countries such as Europe and the United States result in substantial disparities in gastrointestinal metabolism between the two populations. Given this, what should be the criteria for a “good” generic drug?

“The key is to ensure that the drug’s therapeutic effect is released steadily and sustainably within the body. If the release is too rapid, the body cannot tolerate it; if it’s too slow, or if the duration of action is too short, the efficacy will be compromised,” said Sun Lijie. He went on to explain that their primary focus is to achieve a harmonious balance between sustained release and prolonged therapeutic effect—put simply, to have “the best of both worlds.”

“It should be tailored to the physiological characteristics of the Chinese population; ideally, the drug would be released slowly in the stomach and more rapidly in the intestines,” said Sun Lijie.

Over a period of more than six months and through hundreds of round-the-clock experiments, a groundbreaking new formulation gradually emerged: the drug is uniformly coated with a sugar pellet, followed by a composite coating consisting of both sustained-release and enteric materials. This hybrid “magic coat” protects the drug from gastric acid in the stomach, enabling its active ingredients to be released slowly; once it reaches the intestines, the release accelerates, thereby enhancing the body’s absorption.

Urapidil sustained-release capsules achieve long-lasting blood-pressure control with once-daily dosing, significantly surpassing the design standards of the originator product.

Seizing the opportunity, the R&D team filed a national invention patent application for the preparation method of urapidil sustained-release capsules, thereby adding another new entry to Shijiazhuang Sihua Pharmaceutical’s patent portfolio.

The R&D team at Shijiazhuang No. 4 Pharmaceutical has relentlessly pursued the optimal formulation for “China’s medicine,” making steady progress: the Class 1 new drug ADN-9 for combating hepatic fibrosis is advancing smoothly; the generic drugs pentoxifylline sustained-release tablets and stiripentol dry suspension have become the first in China to receive marketing approval; and the specialty API formoterol fumarate has also been approved… Meanwhile, research and development of new drugs in areas such as anti-infectives, the respiratory system, the nervous system, the cardiovascular and cerebrovascular systems, and the digestive system is flourishing across the board.

Since the beginning of this year, Shijiazhuang Sihua Pharmaceutical has obtained approval for 39 new products, bringing the total to 87 varieties and 118 dosage forms that have either passed or are deemed to have passed the consistency evaluation, marking an unprecedented success.

“Producing high-quality medicines for the Chinese people has always been the very soul of Shijiazhuang No. 4 Pharmaceutical’s corporate culture, as well as the guiding principle that drives our employees to serve the nation through industry and give back to society,” said Qu Jiguang, Chairman of the Board of Shijiazhuang No. 4 Pharmaceutical Group. “Science is inherently compassionate. Moving forward, Shijiazhuang No. 4 Pharmaceutical will remain committed to a people-centered approach, continuously innovating and developing more affordable, cutting-edge, and precisely targeted ‘Chinese medicines’ that meet clinical needs and safeguard the health and well-being of the public.”

Keywords:

China Global Television Network (CGTN) Reports on the High-Quality Development of Guangxiang Pharmaceutical, Shijiazhuang Sihua Pharmaceutical Group

Striving to Achieve “More Than Half” in Both Key Metrics | Upholding Innovative Resilience and Unleashing Momentum for Leapfrog Growth: Shijiazhuang No. 4 Pharmaceutical Accelerates Project Construction to Unlock New Production Capacity and Race Toward “More Than Half” in Both Key Metrics

China Global Television Network (CGTN) Reports on the High-Quality Development of Guangxiang Pharmaceutical, Shijiazhuang Sihua Pharmaceutical Group